Leptin, a hormone secreted by the adipocyte, conveys status of energy stores to the brain. Leptin decreases food intake and increases energy expenditure. Deletion of leptin or its receptor results in obesity, hyperphagia, and diabetes. Many forms of obesity in rodents and humans are characterized by increased circulating leptin levels, resulting in a disrupted homeostatic mechanism, evidenced by a failure of the increased leptin levels to reduce food intake and increase energy expenditure. This phenomenon, known as leptin resistance, is seen in both genetic and diet-induced (DIO) models of obesity and in obese humans. Although leptin's major effects are central, it also has effects in the periphery. Leptin resistance has been shown centrally, but resistance to leptin's effects in the periphery has not been studied. Therefore the aim of this proposal is to determine whether resistance to the effects of leptin in DIO is mediated by impairments in leptin signaling pathways in peripheral tissues. Since the AMP-activated protein kinase (AMPK) pathway mediates the effects of leptin on fatty acid oxidation in muscle, we also aim to determine the mechanisms involved in the transduction of the leptin-AMPK signal from the hypothalamus to peripheral tissues. [unreadable] [unreadable] [unreadable]